Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Metabolic Diseases Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Israel.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Mol Genet Metab. 2022 Jun;136(2):101-110. doi: 10.1016/j.ymgme.2022.04.003. Epub 2022 Apr 18.
The NAD(P)HX repair system is a metabolite damage repair mechanism responsible for restoration of NADH and NADPH after their inactivation by hydration. Deficiency in either of its two enzymes, NAD(P)HX dehydratase (NAXD) or NAD(P)HX epimerase (NAXE), causes a fatal neurometabolic disorder characterized by decompensations precipitated by inflammatory stress. Clinical findings include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, while neuroimaging abnormalities are subtle or nonspecific, making a clinical diagnosis challenging. During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation; however, the contribution of each to the metabolic derangement is not established. Herein, we summarize the clinical knowledge of NAXE deficiency from 30 cases and lessons learned about disease pathogenesis from cell cultures and model organisms and describe a metabolomics signature obtained by untargeted metabolomics analysis in one case at the time of crisis and after initiation of treatment. Overall, biochemical findings support a model of acute depletion of NAD, signs of mitochondrial dysfunction, and altered lipidomics. These findings are further substantiated by untargeted metabolomics six months post-crisis showing that niacin supplementation reverses primary metabolomic abnormalities concurrent with improved clinical status.
NAD(P)HX 修复系统是一种代谢物损伤修复机制，负责在其被水合作用失活后还原 NADH 和 NADPH。该系统的两个酶（NAD(P)HX 脱水酶（NAXD）或 NAD(P)HX 差向异构酶（NAXE））之一的缺乏会导致致命的神经代谢紊乱，其特征是炎症应激引发的代偿失调。临床发现包括迅速进展的肌肉无力、共济失调、眼肌瘫痪以及运动和认知功能倒退，而神经影像学异常细微或非特异性，使得临床诊断具有挑战性。在应激状态下，NAD(P)H 会非酶促转化为 NAD(P)HX，而如果没有修复，NAD(P)H 会被消耗，NAD(P)HX 会积累，导致代偿失调；然而，每种物质对代谢紊乱的贡献尚未确定。在此，我们总结了 30 例 NAXE 缺乏症的临床知识，并从细胞培养和模式生物中了解了疾病发病机制的经验教训，描述了在一次危机期间和治疗开始后通过非靶向代谢组学分析在一个病例中获得的代谢组学特征。总的来说，生化发现支持 NAD 急性耗竭、线粒体功能障碍迹象和脂质组学改变的模型。这些发现通过危机后六个月的非靶向代谢组学进一步证实，表明烟酰胺补充可逆转主要代谢异常，同时改善临床状况。
